Nimodipine in Animal Model Experiments
of Focal Cerebral Ischemia
A Systematic Review
J. Horn, MD; R.J. de Haan, PhD; M. Vermeulen, MD; P.G.M. Luiten, PhD; M. Limburg, MD
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Background and Purpose—Based on the results of animal experiments, clinical trials were performed with nimodipine,
which did not demonstrate a beneficial effect on outcome after stroke. The aim of this study was to determine whether
the evidence from animal experiments with nimodipine supported the use of nimodipine in clinical trials.
Methods—We performed a systematic review of animal experiments with nimodipine in focal cerebral ischemia. Studies
were identified by searching Medline and Embase. We assessed whether these studies showed a beneficial effect of
active treatment. In-depth analyses were performed on infarct size and amount of edema, and subgroup analyses were
performed on the length of the time window to the initiation of treatment and the methodological quality of the studies.
Results—Of 225 identified articles, 20 studies were included. The methodological quality of the studies was poor. Of the
included studies, 50% were in favor of nimodipine. In-depth analyses showed statistically significant effects in favor of
treatment (10 studies). No influence of the length of time to the initiation of treatment or of the methodological quality
on the results was found.
Conclusions—We conclude that the results of this review did not show convincing evidence to substantiate the decision
to perform trials with nimodipine in large numbers of patients. There were no differences between the results of the
animal experiments and clinical studies. Surprisingly, we found that animal experiments and clinical studies ran
simultaneously. (Stroke. 2001;32:2433-2438.)
Key Words: animal models 䡲 calcium channel blockers 䡲 cerebrovascular disorders 䡲 nimodipine 䡲 meta-analysis
T
he recognition of the existence of a penumbral zone in
ischemic stroke, as described by Astrup and Siesjo,1 was a
major trigger in the search for an effective neuroprotective agent.
Massive calcium influx into cells was found to be a final common
pathway leading to cell death. Therefore, calcium channel blockers
might protect the penumbral zone from becoming necrotic. Early
steps on the road toward neuroprotective treatments in stroke were,
as usual, in the form of animal experiments. Positive results of
treatment with nimodipine, an L-type calcium channel blocker, in
animal models of acute focal ischemia were reported, and investigations of this agent were started in patients in the early 1980s. In
1988, a randomized controlled trial in stroke patients showed a
beneficial effect.2 On the basis of these promising results, calcium
antagonists in stroke were studied in more clinical trials,3–6 in
which, finally, 7665 patients were randomized. These trials failed to
confirm the beneficial effect of active treatment,7 but in a metaanalysis of 9 trials with nimodipine in acute ischemic stroke, a
statistically significant effect in favor of nimodipine was found
when treatment was started within 12 hours of stroke onset.8 This
again raised hope for neuroprotective treatment in stroke patients.
However, in a recent systematic review performed for the Cochrane
collaboration7 on the effects of calcium antagonists in stroke, this
positive effect of early treatment could not be confirmed.
Similar discrepancies between initial successful experimental animal data and lack of effect in clinical application
have been reported for a variety of potentially neuroprotective drugs. These agents either evoked unacceptable adverse
reactions or did not have any beneficial effect.9 –12 These
disappointing results have raised doubts about the interpretation and validity of the results of animal stroke models with
respect to subsequent clinical research.
The aim of the present investigation was to determine
whether the evidence from animal experiments was in favor
of nimodipine, which would mean that these models were
inadequate in the prediction of treatment response in patients
or that the data were inconclusive, which would mean that the
clinical trials were based on insufficient evidence.
Materials and Methods
Literature Search and Inclusion Criteria
Our literature search for the present review was restricted to
published results of animal studies, which were identified by
Received December 21, 2000; final revision received May 22, 2001; accepted June 15, 2001.
From the Department of Neurology (J.H., M.V.), the Department of Clinical Epidemiology and Biostatistics (R.J.d.H.), and the Department of Medical
Informatics (M.L.), Academical Medical Center, University of Amsterdam, and the Department of Animal Physiology (P.G.M.L.), University of
Groningen, Groningen, the Netherlands.
Correspondence to J. Horn, MD, Department of Neurology, AMC, PO Box 22700, 1100 DE, Amsterdam, Netherlands. E-mail [email protected]
© 2001 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
2433
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Stroke
October 2001
searching Medline (1966 to 1999) and Embase (1980 to 1999) with
the use of the search terms “nimodipine” (limited to “animal”) and
“cerebral ischemia.” Reference lists of identified articles were also
searched.
Studies were included if they fulfilled the following criteria: (1)
the study assessed the effect of nimodipine on focal cerebral
ischemia; (2) a group of control animals was described; (3) nimodipine was administered after the induction of ischemia; (4) the
effect of nimodipine was assessed in animals or in whole brains, not
in slices or samples of brain tissue; (5) nimodipine was not tested in
combination with other neuroprotective agents; (6) there was a
restriction to the original study results (reviews and duplicate
publications were excluded); and (7) the studies were published in
English, French, or German. The selection of trials (unblinded) was
performed (by J.H.) on the basis of title and abstract. In case of
doubt, the whole publication was evaluated.
Data Extraction
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From the included studies, the following data were extracted: animal
species; number of animals in treated and control groups; method of
allocation to treatment group; method to induce ischemia; method,
dosage, and time of drug administration; method to assess efficacy
(blinded assessment); and results of treatment.
TABLE 1.
Reasons for Exclusion of Articles (Total 205)
Reason for Exclusion
No. of Trials (%)*
Global ischemia
52 (25)
Treatment started before ischemia
35 (17)
Review article
31 (15)
Effect assessed in brain tissue slices
21 (10)
No nimodipine used in experiment
18 (9)
No ischemia induced
15 (7)
Language
11 (5)
About subarachnoid hemorrhage
10 (5)
Duplicate publication
6 (3)
No control group
5 (2)
Unable to achieve manuscript
1 (0)
*Because of rounding, the sum of percentages is not 100.
For each study, we defined whether a positive (nimodipine beneficial) or negative (no difference between active and placebo treatment
or deleterious effect of nimodipine) result was reported.
Analysis in depth was possible only for a limited selection of
trials, which reported data on the impact of nimodipine on infarct
size or amount of edema. Per study, we calculated the effect size (the
mean of the treatment group minus the mean of the control group
divided by the pooled standard deviation of the 2 groups) and pooled
the individual effect sizes accordingly. Because our data was shown
to be heterogeneous, we used a random-effects model.14 Statistical
uncertainty was expressed in 95% CIs.
nimodipine in global ischemia models or because nimodipine
was administered before the induction of ischemia. We also
identified several duplicate publications.16 –24
Twenty studies fulfilled the inclusion criteria; the characteristics of these studies are listed in Table 2, in which the
studies are ordered by increasing length of the time interval
between the induction of ischemia and the initiation of
treatment. In total, 234 animals were treated with nimodipine
(216 animals served as controls) after the induction of focal
cerebral ischemia. In all studies, the animals were anesthetized during the surgical procedures, only 1 study explicitly
reported that the animals were allowed to recover before the
induction of ischemia.25 Parameters such as body temperature, blood glucose levels, and blood pressure were maintained within strict limits in most animal experiments.
In 12 of 19 studies, treatment was started within 1 hour
after the induction of ischemia.16,21,25–34 One study did not
state the length of this interval.35 The methodological quality
of the included studies was poor (median 2.85 points, range 1
to 5). Only 2 studies mentioned randomization of the animals,27,33 and in 6 studies, the outcome was assessed by a
blinded assessor.21,25,26,28,32,36 One study reported “doubleblind” assessment of effectiveness.37 Although 9 studies
assessed 2 outcome measurements (functional and histopathologic),18,25,27,32,35–39 only 3 studies assessed outcome
in the chronic phase.18,32,36
Subgroup Analyses
Outcome
In view of the common opinion that treatment has to be started as
soon as possible after the induction of ischemia,15 we performed a
subgroup analysis on data from studies in which nimodipine was
started within or later than 1 hour after ischemia. Difference in the
frequency of treatment results was analyzed with the Fisher exact
test. Finally, we investigated whether study methodology influenced
the results of the experiments.
Of the 20 included studies, 10 reported a positive effect of
nimodipine, and 10 did not. In 7 studies, exact data about
infarct size were presented21,28 –31,36,37 (Figure 1). The pooled
effect size in favor of nimodipine was ⫺1.2 (95% CI ⫺1.7 to
⫺0.7).
Extracting data regarding the amount of edema was possible in 3 studies18,27,34 (Figure 2), revealing a pooled effect size
of ⫺0.6 (95% CI ⫺1.2 to ⫺0.1) in favor of nimodipine.
Methodological Quality of Studies
On the basis of recommendations published in 1999,13 we designed
an 8-point rating system to assess the methodological quality of the
included animal experimental studies. One point was attributed for
each of the following characteristics: (1) the dose/response relationship that was investigated, (2) randomization of the experiment,
(3) optimal time window of the treatment investigated, (4) monitoring of physiological parameters, (5) blinded outcome assessment, (6)
assessment of at least 2 outcomes (infarct size and 1 functional
outcome), (7) outcome assessment in the acute phase (1 to 3 days),
and (8) outcome assessment in the chronic phase (7 to 30 days). The
points were granted when in the study report these items were
mentioned. Studies scoring ⬍4 points were graded as “poor methodological quality,” and studies with ⱖ4 points were scored as “good
methodological quality.”
Outcome Assessment and Statistical Analyses
Results
Description of Studies
We identified 225 articles. On the basis of predefined criteria,
205 articles were excluded (a list of these studies is available
from the author). Table 1 lists the various reasons for exclusion.
Many studies were excluded because they described the effect of
Subgroup Analysis
Additional analysis of the studies in which treatment was
started within 1 hour after the induction of ischemia resulted
in 4 positive and 8 negative studies. Treatment that was
Horn et al
TABLE 2.
Systematic Review of Nimodipine in Animal Studies
2435
Characteristics of 20 Included Studies (Ordered by Length of Time Interval Between Ischemia and Start of Treatment)
Result
(Methodological
Score)
First Author,
Year of
Publication
Animal
(Treated/Control),
n
Bartkowski,
1988
Rats (31/23)
MCA occlusion, unknown which
method and whether permanent or
not
20 ␮g/kg per h IV for 24 h,
started after occlusion (time
window unknown)
Neurological outcome and infarct size
24 h after occlusion
Positive (3)
Meyer,16
1986
New Zealand
White rabbits
(10/10)
Surgical occlusion of MCA,
permanent
0.5 ␮g/kg per min IV for 4 h
immediately after occlusion
CBF, intracellular brain pH, and EEG
amplitude measurement until 4 h after
occlusion
Positive (1)
Snape,26
1993
Lister hooded
rats (8/4)
Photochemically induced
cortical infarction
0.5 mg/kg IP 5 min after
irradiation
Size of infarcted area 24 h after
surgery
Negative (3)
Greenberg,21
1990
Cats (8/6)
Microsurgical occlusion of left
MCA for 1 h (3-h reperfusion)
5 ␮g/kg per min for 3 min and 1
␮g/kg per min until end of
reperfusion, IV started 5 min after
occlusion
Infarct size, cytosolic free calcium,
amplitude depression on EEG, 4 h after
occlusion
Positive (3)
Lyden,25
1988
New Zealand
White rabbits
(34/18)
Anesthesia, injection of
microspheres into CCA (ECA
ligated)
5 or 50 ␮g/kg for 2 min, IV
started 5 min after injection of
microspheres
Neurological outcome (normal,
abnormal, or dead) after 18 h (blinded
assessment!)
Negative (4)
Deng,27
1997
Wistar rats
(10/14)
Occlusion of right MCA (Tamura
method), permanent
5 mg/kg SC, started 5 min
after occlusion
Neurological deficit, amount of brain
edema, 24 h after occlusion
Positive (3)
Gotoh,28
1986
Sprague-Dawley
rats (5/5)
Occlusion of MCA (Tamura
method), permanent
1 ␮g/kg per min IV until death,
started 5 min after occlusion
Volume ischemic damage, 4 h after
occlusion and local CBF (35 min after
occlusion)
Negative (3)
Berger,30
1989
Sprague-Dawley
rats (7/7)
Surgical occlusion of left MCA,
permanent
0.5 ␮g/kg per min IV for 4 h,
started 15 min after occlusion
Infarct volume, local cerebral pH and
local CBF, 4 h after occlusion
Negative (2)
Berger,29
1988
Sprague-Dawley
rats (5/6)
Surgical occlusion of left MCA,
permanent
0.5 ␮g/kg per min IV for 75 min,
started 15 min after occlusion
Infarct volume, local cerebral pH and
local CBF, 75 min after occlusion
Positive (2)
Hakim,31
1986
Sprague-Dawley
rats (4/8)
Occlusion of left MCA (Tamura
method), permanent
0.5 ␮g/kg per min IV, started
15 min after occlusion
Infarct size, local cerebral pH and local
CBF, 3 h after occlusion
Negative (2)
Sauter,32
1986
SHR/KYO rats
(6–8/8)
Surgical coagulation of left
MCA, permanent
Bolus 0.6 mg/kg per d SC, 15,
105, and 195 min after
occlusion
Neurological score (blinded observer), MRI
to assess infarct size, biochemical analysis,
3 d after occlusion
Negative (4)
Dirnagl,33
1990
Wistar rats (8/8)
Surgical occlusion of right CCA and
MCA, permanent
2 ␮g/kg per min IV for 60 min,
started 30 min after occlusion
Changes in cortical microcirculation
Negative (2)
Nishikibe,34
1988
Mongolian
gerbils (17/24)
Surgical occlusion of left CCA,
permanent
0.01 or 0.1 mg/kg IP, bolus
injection, administered 30 min
after occlusion
Regional CBF and MAP in 3 types of
ischemic severity
Negative (2)
Selcuklu,36
1993
New Zealand
White rabbits
(6/6)
Surgical occlusion of ICA,
permanent
1 ␮g/kg per d IV (3 animals
treated for 6 h, 3 treated for
24 h), started 1 h after
occlusion for both groups
Blinded neurological examination,
infarct volume, volume of edema, 7 d
after occlusion
Positive (5)
de la
Torre,55
1991
Cats (4/4)
Surgical ligation of MCA,
permanent
1 ␮g/kg per min for 60 min IV
started 1 h after occlusion
Rate of cytoprotection and CBF, 4 h
after occlusion
Negative (2)
Germano,38
1986
Sprague-Dawley
rats (5/5)
Microsurgical coagulation of
MCA, permanent
20 ␮g/kg for 10 min, IV started
1 h after occlusion
Neurological evaluation, MRI, and
histopathologic assessment of infarct
size, 12 h after occlusion
Positive (3)
Germano,37
1987
Sprague-Dawley
rats (24/24)
Surgical transsection of left
MCA, permanent
2 ␮g/kg per min IV for 10 min,
started 1, 2, or 3 h after occlusion
(n⫽8 in each group)
Neurological evaluation (double blind)
and infarct size, 24 h after occlusion
Positive (5)
Kobayashi,39
1988
Rats (26/26)
MCA occlusion, unknown which
method and whether permanent or
not
20 ␮g/kg IV, 1 or 4 h after
occlusion
Neurological outcome and infarct size,
24 h after occlusion
Negative (3)
Roda,56
1995
Long-Evans rats
(5/5)
Permanent right MCA occlusion
and 90-min occlusion of both
CCAs, 24-h reperfusion
40 ␮g/kg IA as bolus given
twice, 90 min and 110 min
after occlusion
Infarct size 24 h after occlusion
Positive (2)
Hara,18
1990
Wistar rats
(11/15)
Occlusion of left CCA for 3 h
(3-h reperfusion)
30 ␮g/kg and 6 mL/kg IV, started
3 h after occlusion, at pump rate
0.2 mL/min for 30 min
Mortality (after 7 d), neuronal damage,
and brain edema (6 h after occlusion)
Positive (3)
35
Method of Ischemia
Method of Administration
Assessment
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SHR indicates spontaneously hypertensive rats; KYO, Kyoto; MCA, middle cerebral artery; CCA, common carotid artery; ECA, external carotid artery; ICA, internal
carotid artery; CBF, cerebral blood flow; and MAP, mean arterial pressure.
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October 2001
Figure 1. Results of in-depth analysis on infarct size. SMD indicates standardized mean difference (effect size).
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started ⱖ1 hour after the induction of ischemia resulted in 5
positive and 2 negative studies (P⫽0.17).
In the 4 studies with a good methodological quality,25,32,36,37 2 showed an effect in favor of nimodipine, and 2
did not.
Discussion
In the present investigation, we focused on whether the
evidence from animal experiments was in favor of nimodipine, which would mean that these models were inadequate to
predict the treatment response in patients or that the data from
animal experiments were inconclusive, which would mean
that the clinical trials were based on insufficient evidence.
The selected studies did not provide an answer regarding the
efficacy of treatment with nimodipine (50% of the studies
were in favor of nimodipine). Nor did subgroup analyses on
the length of the time window to treatment and the methodological quality of the studies demonstrate beneficial treatment results. Because we had no information that time
window to treatment would differ between different animal
models, we decided not to speculate and performed the rough
time analysis as presented. More detailed subgroup analyses
on the effects of different doses of nimodipine or infusion
periods could not be performed because of the small number
of included studies. In-depth analyses on the effect of
nimodipine on infarct size and the amount of edema showed
statistically significant beneficial results. These data could be
extracted only from a small subsample of publications, which
turned out mainly to be reports with positive treatment
results. However, this supports the fact that both infarct size
and functional outcome should be assessed in animal experiments of focal ischemia.
We found that the methodological quality of the included
studies was poor. Issues such as randomization, masked
treatment allocation, blinded outcome assessment, and intention to treat analyses, which are very important issues and are
now generally required in clinical studies, were especially
neglected in these animal experiments.40 Surprisingly, 1 study
reported a double-blind assessment of effectiveness.
We realize that systematic reviews carry hazards such as
publication bias and a bias for good quality studies.41,42
Evaluating “old” studies from the early 1980s increases these
hazards. Because most experiments were performed ⬎10
years ago, we did not approach the authors for detailed
information about their studies. We considered it to be
unlikely that the authors either possessed or would remember
the data required. By limiting our search strategy to the
electronic databases and the reference lists of articles, we
were unable to estimate the number of unpublished manuscripts. For clinical trials with calcium antagonists in ischemic stroke, we found that at least 18% of all studies remained
unpublished.7 In these unpublished trials, results were significantly worse for patients in the treatment group. One might
assume that in experimental animal research, this percentage
would not be different. If such a publication bias for negative
animal experiments exists, this would result in an even more
“negative” conclusion of the present review. Other possible
sources for bias are selection of studies and data extraction.
Figure 2. Results of analysis on amount
of edema.
Horn et al
Systematic Review of Nimodipine in Animal Studies
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The fact that this was done by 1 author might have increased
this risk; however, criteria for study inclusion and data
extraction were strict. The number of manuscripts written in
a “foreign language” (ie, Chinese, Japanese, Russian, or
Polish) was limited (2%). We assumed that translating these
manuscripts would not result in more useful data.
Was the animal model used suitable to predict the effectiveness of nimodipine in stroke patients? Several authors
have discussed the discrepancies between the results of
animal models in stroke and the results of clinical studies.43– 48 A possible explanation for these discrepancies was
the difference in the age of the patients. Older stroke patients
often have comorbidity, such as diabetes and hypertension.
Furthermore, in animal experiments, physiological parameters (blood pressure, [brain] temperature, and blood glucose
levels) can be kept within strict limits, and neuroprotective
treatment can be started immediately or shortly after the
induction of ischemia. Finally, major differences exist in the
assessment of the effectiveness of animal experiments measuring histopathologic parameters compared with trials measuring functional ability in stroke patients.
Results of animal experiments with nimodipine in focal
cerebral ischemia were reported until 1997, which was 15
years after the first clinical study. It is surprising that these
animal experiments ran a course parallel to several clinical
studies, because it is reasonable to assume that the clinical
studies are preceded by animal studies. However, as early as
1982, the first results of clinical studies on the effect of
nimodipine on cerebral blood flow in stroke patients were
reported.49 On the basis of the hypothesis of the calciumdependent final common pathway in cell death and his
previous experiments, an author started a “single-blind” pilot
study, which showed that treatment with nimodipine was
promising.50 In 1988, the same author reported the results of
a placebo-controlled, double-blind, randomized clinical trial.2
In the introduction to his article, results of animal experiments with nimodipine were quoted. Only 1 experiment dealt
with focal cerebral ischemia28; others concerned global ischemia or the use of nimodipine before the induction of ischemia. The authors concluded that nimodipine was statistically
significantly better than placebo regarding mortality and
changes in neurological deficit (modified Mathew scale).
However, repeat analysis of data on the functional outcome of
patients in this trial, by dichotomizing the score on the
disability item in the modified Mathew scale, shows a
difference that was not statistically significant.7 The supposedly positive results of this first randomized controlled trial
were followed by a small trial,51 which showed similar
results. In the introduction to that article, the authors refer to
an animal experiment by Germano et al.52 Subsequent reports
on larger clinical trials3,4,53,54 refer in the introduction to a
single positive animal experiment, to the proven effectiveness
of nimodipine in the treatment of subarachnoid hemorrhage,
and primarily to the positive results of the first randomized
controlled trial with nimodipine in ischemic stroke.
We conclude that the results of the animal experiments
reviewed in the present investigation did not show convincing
empirical evidence to substantiate the decision for trials with
nimodipine in stroke patients. In fact, there were no differ-
2437
ences between the results of animals experiments and clinical
studies. Surprisingly, we found that animal experiments and
clinical studies ran simultaneously.
Acknowledgement
We want to thank Dr P.J. Assendelft for critically reading the
manuscript and giving advice.
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J. Horn, R.J. de Haan, M. Vermeulen, P.G.M. Luiten and M. Limburg
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Stroke. 2001;32:2433-2438
doi: 10.1161/hs1001.096009
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